SAFE COADMINISTRATION OF TERBINAFINE AND TERFENADINE - A PLACEBO-CONTROLLED CROSSOVER STUDY OF PHARMACOKINETIC AND PHARMACODYNAMIC INTERACTIONS IN HEALTH VOLUNTEERS

The pharmacokinetic and pharmacodynamic interactions of terbinafine (L amisil) and terfenadine (Seldane) were assessed in 26 healthy voluntee rs randomized to receive either terbinafine (250 mg tablet) or its pla cebo (terbinafine placebo), which were administered in a double-blind manner once daily for 18 days. On days 12 through 18, terfenadine was coadministered (60 mg twice daily, unblinded), Pharmacokinetic profile s were obtained for terbinafine and its desmethyl metabolite on day 11 (in the absence of terfenadine), day 12, and day 18, Terfenadine and terfenadine acid metabolite levels were also assayed on days 12 and 18 , After a 4-week washout period, subjects were crossed over to the alt ernate treatment (terbinafine or terbinafine placebo). Pharmacodynamic measures were electrocardiographic (EGG) rhythm abnormalities, correc ted QT interval (QT(c)), and plasma ALT levels. Terfenadine levels wer e evaluated; however, only eight of 1502 samples assayed were above th e limit of quantitation, No effect of terbinafine administration on ph armacokinetic parameters for the terfenadine acid metabolite was obser ved, except for a decrease of approximately 20% in trough terbinafine concentrations (C-0hr;p < 0.05) on the last day of terfenadine plus te rbinafine coadministration. Pharmacokinetic parameters for terbinafine were unchanged on the first day of terfenadine coadministration, and only small increases in area under the plasma concentration versus tim e curve from 0 to 24- hours and peak plasma concentrations (16.1% [p < 0.01] and 6.63% [P < 0.05]) were observed on the last day of terfenad ine and terbinafine coadministration, Values for C-0hr also about 20% to 25% higher (p < 0.05). Steady-state levels of the terfenadine acid metabolite were achieved after 2 days of terfenadine coadministration, and steady-state levels of terbinafine and its desmethyl metabolite w ere achieved after 14 days of terbinafine administration. The incidenc e of ECG rhythm abnormalities was not significantly higher in any trea tment group; however, the incidence of prolongation of QT(c) > 10% abo ve baseline was significantly higher in the groups treated with terfen adine. No QT, prolongation occurred in the absence of terfenadine trea tment. Both terbinafine and terfenadine were well tolerated when coadm inistered during this study, as indicated by the low incidence of comp laints, abnormalities, and adverse events, The results of this study i ndicate that terbinafine and terfenadine can be safely coadministered.